The specific contribufion of different primary sensory neurons in producing pain and itch will be invesfigated by targeted delivery of an impermeant cafionic sodium channel blocker (QX-314, a quaternary derivative of lidocaine) through large-pore ion channels differenfially expressed on afferents. The aim is to electrically silence subsets of axons using combinafions of QX-314 and large-pore ion channel agonists. We have validated this strategy for TRPV1-expressing nociceptors using capsaicin and QX-314 to produce a long lasfing pain-specific local anesthesia, and our pilot data suggest that TRPAl and P2X3 activafion by mustard oil and ATP also allow QX-314 permeation into DRG neurons. We will confirm this using whole cell patch clamp recordings in DRG neurons. The strategy will then be used in vivo to determine the funcfional effects on nociception of blocking TRPVl, TRPAl and P2X3 expressing nociceptors in naive rats and mice, measuring behavioral deficits in response to speciflc mechanical, thermal and chemical sfimuli. The afferent silencing strategy will also be used to idenfify which large-pore ion channel expressing primary afferents contribute to histaminergic and non-histaminergic itch. The presence of silenced afferents after administering QX-314 alone will be used to establish if large-pore ion channels are consfitufively acfivated by endogenous agonists during peripheral inflammafion, after nerve injury, in acute and chronic itch, when, and where. Our pilot data show that QX-314 blocks nociceptor terminals in the presence of inflammafion but not in naive animals. We will now explore if QX314 administered to peripheral terminals or nerves alters different modalifies of pain sensitivity in soft fissue, incisional, arthrific, and peripheral neuritic inflammatory models, as well as in neuropathic pain and pruritic atopic dermafitis models. These strategies will help both identify the cellular mechanisms of nocicepfive, inflammatory and neuropathic pain, acute and chronic itch and develop opportunifies for targeted novel therapeutic interventions to treat these condifions. RELEV/VNCE (See instmctions): We propose to develop a new analgesic strategy; targeting the pain pathway in the periphery using large- pore lon channels specific to the system as a means of delivering a sodium channel blocker only into defined sets of neurons. The proposal will test the potential of this appraoch for acute and chronic pain therapy.